Targeting an extracellular epitope of the human multidrug resistance protein 1 (MRP1) in malignant cells with a novel recombinant single chain Fv antibody

Inherent and acquired multidrug resistance (MDR) is characterized by a simultaneous resistance to diverse anticancer drugs and is a major impediment towards curative chemotherapy of cancer. Hence one important goal is to develop strategies aimed at specific targeting of major anticancer drug efflux transporters of the ATP-binding cassette (ABC) superfamily including multidrug resistance protein 1 -MRP1 (ABCC1). To date, no monoclonal antibody has been isolated that can target an extracellular MRP1 epitope. Using a phage display approach, we have isolated a recombinant single-chain Fv (scFv) antibody that specifically reacts with the extracellular N-terminus of the human MRP1. Flow cytometric analysis revealed that this scFv fragment binds specifically to various viable human tumor cells that display variable MRP1 expression levels but not to MRP1 null cells. Furthermore, this scFv antibody failed to react with tumor cells that overexpress other members of the MRP family that have an extracellular N-terminus (MRP2 and MRP3) as well as with MRP4, MRP5, and breast cancer resistance protein. Flow cytometric analysis also showed a good correlation between the fluorescence intensity of the anti-MRP1 scFv antibody and MRP1 levels in viable tumor cells. These findings constitute the first successful isolation of a small recombinant scFv antibody directed to an extracellular epitope of the MRP1 in viable malignant cells. These novel small Fv-based recombinant antibodies that possess superior tumor penetration capabilities may possibly be used to selectively target drugs or tumor cells that express MRP-1.     

Amelioration of behavioral deficits in a rat model of Huntington's disease by an excitotoxic lesion to the globus pallidus

Four groups of rats, sustaining a striatal quinolinic acid (QA) lesion, a pallidal QA lesion, a combined striatal + pallidal lesion, or sham operation, were tested in spontaneous and amphetamine-induced activity, spatial navigation in a water maze, position discrimination and reversal in a wet T maze, and food manipulation. The striatal lesion markedly impaired rats' performance on the motor and cognitive tasks. In contrast, rats sustaining a bilateral lesion to the GP in addition to the striatal lesion performed similarly to sham-operated rats on the motor and cognitive tasks, although they showed a transient decrease in activity levels. Given that a similar dysfunction of basal ganglia circuitry is thought to subserve the behavioral alterations seen in QA-lesioned rats and Huntington's disease (HD) patients, the present results raise the possibility that manipulations of the external segment of the globus pallidus (the primate analogue of the rat GP) could ameliorate some of HD symptoms.     

Do oral contraceptives improve vocal quality? Limited trial on low-dose formulations

OBJECTIVE: To evaluate the effect of low-dose monophasic oral contraceptives on female vocal quality. METHODS: Acoustic voice parameters of six women who use oral contraceptives and six women who do not were evaluated repeatedly during the menstrual cycle. Frequency and amplitude variations were measured using a computerized voice analysis program. Repeated-measures analysis of variance was performed to test differences between groups for each acoustic voice parameter. RESULTS: Vocal stability among the women who use oral contraceptives was significantly better than among those who did not use oral contraceptives (P <.05). Specifically, amplitude and frequency variations between successive vocal cycles were smaller in women using oral contraceptives in comparison with the control group (.24 dB versus.37 dB and.86% versus 1.27% for amplitude and frequency variations, respectively). CONCLUSION: Contrary to the reports of adverse effects that high-dose pills have on voice, low-dose oral contraceptives show a favorable influence on voice in young women.     

The effect of training on frequency discrimination: generalization to untrained frequencies and to the untrained ear

While there is growing evidence that frequency discrimination improves with practice, there are, however, limited and inclusive reports regarding the generalization of learning to untrained conditions. The goals of the present study were therefore (1) to measure the effect of multi-session training on difference limen frequency (DLF) thresholds and evaluate the relative contribution of procedural and stimulus learning by comparison to a control (untrained) group; (2) to evaluate the extent of generalization of the trained frequency to two untrained frequencies known to be temporally coded; and (3) to estimate the generalization of the trained frequency to the untrained ear, for both trained and untrained frequencies. Two groups of subjects were included: a trained group (n = 5) and a control group (n = 5). For the trained group, DLF thresholds for 1 kHz (trained frequency) and 1.1 and 2.0 kHz (untrained frequencies) were obtained using a two-interval, two-alternative forced choice paradigm before and after an eight-session training. The control group was tested using the same stimuli only twice, with a 3-week interval between testing. Results showed that (1) multi-session training improves frequency discrimination in normal hearing young adults; (2) adding a control group to the study allowed estimation of the effect of limited exposure to the stimuli and task in na?ve listeners and evaluation of the magnitude of procedural learning; (3) learning was generalized across frequencies that are coded by similar mechanisms; (4) generalization of learning occurred in the untrained ear for trained and untrained frequencies. These results have important clinical and theoretical implications regarding the processes underlying perceptual learning and the effectiveness of auditory habilitation strategies.     

Effect of second-formant transitions on the perception of Hebrew voiced stop consonants

Studies in English, Dutch, Danish and French show that of the possible acoustic cues that listeners use for the perception of place of articulation, the transition of the second formant (F2) appears to be a very important cue. Although the Hebrew language shares some similarities with the above languages, one cannot assume that it either has similar acoustic-articulatory patterns or uses the same cues for perception. The general goal of the present study was, therefore, to investigate the effect of the starting frequency of F2 transition on the perception of place of articulation of Hebrew voiced plosives in initial position. Sixteen Hebrew-speaking young normal-hearing adults served as subjects. Stimuli were generated by re-synthesizing a naturally spoken /ba/ syllable into 17 test syllables by varying only the starting frequency of F2. Listeners heard each stimulus six times (total of 102) at random and were required to label the stimuli as /ba/, /da/ or /ga/. Results showed that varying only F2 transitions caused a perceptual change of place of articulation for all listeners. There was, however, large inter-subject variability in the perceived category: 75% of the subjects identified /ba/ and /da/, half of them also identified /ga/, and 25% of the subjects were able to identify /ba/ and /ga/ only. These data suggest that while F2 transitions are important for perceiving place of articulation of Hebrew voiced stops, they cannot predict the perceived category. It also supports the notion that normal-hearing listeners differ in the relative importance they assign to the cues for the perception of place of articulation.     

Women empower women: volunteers and their clients in community service

The study is aimed at examining the relationship between psychological empowerment of women volunteers and their clients in community volunteer projects in Israel. Based on an ecological approach, the study also aimed at examining whether the variables that explain empowerment of women who volunteer also explain empowerment of their clients. The sample included 148 women, who were divided into 74 volunteer‐client pairs. Psychological empowerment of volunteers did not correlate significantly with psychological empowerment of clients. However, the volunteer women's motives for volunteering and the quality of the volunteer–client interaction correlated positively with psychological empowerment of the clients. Empowerment of volunteers was explained primarily by social motives, by the quality of interactions with their clients, and by the quality of the volunteer's interaction with the coordinator of volunteer activity. In light of the findings, practical recommendations are offered for empowering women volunteers and their clients in community settings. © 2011 Wiley Periodicals, Inc.     

Insulin resistance and parental obesity as predictors to response to therapeutic life style change in obese children and adolescents 10-18 years old

OBJECTIVE: To study insulin resistance and parental obesity as predictors of improvement in weight status in obese children and adolescents undergoing therapeutic life change intervention (TLC). DESIGN: A retrospective chart review. SUBJECTS: One hundred thirty-four adolescents 10 to 18 years old above the 95th percentile for body mass index (BMI), referred to the Center for Atherosclerosis Prevention from January through December 2003. MEASUREMENTS: BMI, fasting insulin, homeostasis model assessment insulin resistance (HOMA-IR). Weight management success was defined as BMI Z-score at final exam minus BMI Z-score at initial exam 相似文献   

Three‐Dimensional Ultrasonography of the Fetal Vermis at 18 to 26 Weeks' Gestation

Objective. The purpose of this study was to establish the normality of the fetal vermis, ie, the time of appearance of the primary fissure, as well as its measurements between 18 and 26 weeks' gestation, using 3‐dimensional (3D) ultrasonography. Methods. A prospective cross‐sectional study of normal singleton pregnancies was conducted. Examinations were performed with high‐resolution transabdominal ultrasonography using the axial plane in 173 fetuses between 18 and 26 weeks' gestation. Postprocessing measurements of the fetal vermis were done with 4‐dimensional software using static volume contrast imaging and tomographic ultrasound imaging in the C‐plane. Detection of the primary fissure was evaluated in all cases, and the time of appearance was documented. Results. Adequate vermis measurements were obtained in 173 fetuses. Vermian length as a function of gestational age was expressed by regression equations, and the correlation coefficients were found to be highly statistically significant (P < .001). The normal mean ± 2 SD for each gestational week was defined. The primary fissure was observed at 24 weeks' gestation in all cases, at 22 weeks in 94% of cases, and as early as 18 weeks in 40%. Conclusions. This 3D study documents the appearance of the primary fissure and presents the normal range of vermian measurements, confirming normal development of the fetal vermis starting as early as 18 weeks' gestation. It also shows an easy method for visualizing the vermis with 3D ultrasonography at every gestational week regardless of fetal presentation.